Respiratory Research (2021) 22:76 https://doi.org/10.1186/s12931-021-01666-3
Alberto Ricci1,2, Alessandra Pagliuca1,2, Michela D’Ascanio1,2, Marta Innammorato1,2*,
Claudia DeVitis2, Rita Mancini2, Simonetta Giovagnoli2, Francesco Facchiano4, Bruno Sposato5,
Paolo Anibaldi2, Adriano Marcolongo2, Chiara De Dominicis2, Andrea Laghi2, Emanuele Muscogiuri2 and Salvatore Sciacchitano1,3
Note: Many other studies have found that higher vitamin D levels are needed: 40 to 150 ng
A 30 ng vitamin D level is not sufficient for many diseases
COVID-19 mortality extrapolates to zero at 50 ng of vitamin D – 18th Meta-analysis Sept 2021
- As of Oct42, 2022, the VitaminDWiki COVID page had: 19 trial results, 37 meta-analyses and reviews, Mortality studies see related: Governments, HealthProblems, Hospitals, Dark Skins, 26 risk factors are ALL associated with low Vit D, Recent Virus pages Fight COVID-19 with 50K Vit D weekly Vaccines Take lots of Vitamin D at first signs of COVID 116 COVID Clinical Trials using Vitamin D (08/2022)
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c19study.com/d Summary of Vitamin D and COVID studies (the following is updated automatically)
Background: Several immune mechanisms activate in COVID-19 pathogenesis. Usually, coronavirus infection is characterized by dysregulated host immune responses, interleukine-6 increase, hyper-activation of cytotoxic CD8T lymphocytes. Interestingly, Vitamin D deficiency has been often associated with altered immune responses and infections. In the present study, we evaluated Vitamin D plasma levels in patients affected with different lung involvement during COVID-19 infection.
Methods: Lymphocyte phenotypes were assessed by flow cytometry. Thoracic CT scan involvement was obtained by an image analysis program.
Results: Vitamin D levels were deficient in (80%〇) of patients, insufficient in (6.5%〇) and normal in (13.50/〇). Patients with very low Vitamin D plasma levels had more elevated D-Dimer values, a more elevated B lymphocyte cell count, a reduction of CD8+T lymphocytes with a low CD4/CD8 ratio, more compromised clinical findings (measured by LIPI and SOFA scores) and thoracic CT scan involvement.
Conclusions: Vitamin D deficiency is associated with compromised inflammatory responses and higher pulmonary involvement in COVID-19 affected patients. Vitamin D assessment, during COVID-19 infection, could be a useful analysis for possible therapeutic interventions.
The present study compared, for the first time, VitD plasma levels with different health related scores, inflammatory markers, markers of cellular damage and coagulation and radiological findings during COVID-19 illness. Interestingly, patients with low VitD plasma levels had compromised biochemical and clinical findings reflected by the profound immunological involvement. Vitamin D insufficiency and deficiency were common in COVID-19 affected patients. About 8% of the study cohort had normal VitD plasma levels. Patients with more severe COVID-19 disease had lower Vit D plasma levels regardless of age.
VitD plasma levels are the most accurate markers for defining VitD state. 25(OH)D is the major form of circulating of VitD and it is the one measured. In general, in population VitD levels lower than 20 ng/mL (50 nmol/L) are commonly considered as deficiency status. Moreover, levels ranging 20 to 29 ng/mL (52-72 nmol/L) should define insufficiency, while levels above 30 (75 nmol/L) sufficiency . Moreover, these levels are strictly related to VitD effects on bone metabolism, while VitD levels useful for investigation of other aspects of human health are under investigation [10, 20]. For a long time, 10 ng/ml has been considered the VitD level for defining deficiency [21, 22]. Although the Endocrine Society has defined 20 ng/ml VitD plasma levels, in terms of 25(OH)D, as the threshold to define the deficiency status  there are insufficient evidences to clarify the optimal plasma VitD concentration necessary for the global well-being [23-25].
From a general point of view, VitD activity also seems essential in the regulation of oxidative stress and survival mechanisms . Furthermore, a broad number of studies suggests the role of VitD not only as a simple micronutrient, linked to calcium homeostasis, but as a pluripotent hormone which has extensive immunomodulatory functions . The respiratory alveolar epithelium represents the first line of defense able to counteract and prevent the entry of inhaled pathogens. It represents one of the main actor of the innate immunity including alveolar macrophages and dendritic cells. If stimulated, these cells activate a variety of intracellular signaling pathways for specific antimicrobial defenses, release of inflammatory mediators and adaptive immune responses . Adaptive immune response is strictly related to the ability of T and B lymphocytes to secrete cytokines and produce immunoglobulins respectively . VitD deficiency has been correlated with increasing levels of IL-6, while VitD supplementation down regulates IL-6 levels in several studies . IL-6 is elevated in COVID-19 patients with severe disease and it is also considered a relevant prognostic marker. It has been reported that mortality is higher in patients with elevated levels of IL-6. Therefore, IL-6 and IL-6R are receiving more attention as potential therapeutic targets for the treatment of COVID-19. In our COVID-19 infected patient group we have documented elevated IL-6 levels, upper the normal limits, in almost all the patients. Unfortunately, large variability among them was documented. Therefore, no correlation was detectable between VitD and IL-6 values in this cohort of patients. Moreover, in patients with very low VitD levels, the IL-6 values was slightly, but not significantly, more elevated in comparison with patients with higher VitD levels. This result may be attributed to sample size.
Elevated neutrophil count predicts ongoing inflammation and decreased lymphocyte count is considered an indicator of poor prognosis. A combination of these two measures, and the derived NLR ratio dNLR, are considered predictive of an inflammatory status. In acute Covid-19 disease, the more severe status is often associated with increased neutrophil cell count and a reduction of lymphocytes. Both CD4 T-helper and CD8 T-cytotoxic lymphocytes may be affected, with a CD4 more severe reduction associated with more severe disease and worst prognosis. In our patients, a moderate correlation was observed between CD4 + /CD8 +ratio, CD8 +count and VitD plasma levels. In addition, a statistically significant difference was detected between patients with low VitD plasma levels in comparison with those with more elevated VitD levels in both CD4 + /CD8 +and CD8 cell count. More elevated CD4/CD8 ratio was detected in patients with low VitD plasma levels. T-lymphocytes are essential in coordinating several immune functions, helping macrophages and B lymphocytes to counteract the development of the disease. The disease-induced loss of lymphocyte activity markedly weakens the immunological responses. Although, the causes of peripheral blood lymphocyte (PBMC) suppression were under investigation, no viral gene expression was detected in PBMC and no COVID-19 virus infection was demonstrated in these cells . Their reduction may be the result of migration/ compartmentalization to the site of damaged tissue . In fact, the T CD8 + cell expansion into the lung of mild symptomatic COVID patients, assessed by bronchoalveolar lavage has been described .
Categorizing patients as a function of TC Score analyzing lung findings obtained by high resolution computer tomography, we demonstrated that lower plasma levels of Vit D are strictly related with an increase lung involvement characterized by more diffuse ground glass opacities within the lung. This condition reflects more severe disease linked to the redundant and dysfunctional immunological responses described. The same is true describing the sequential organ failure assessment (SOFA) score. It allows us to assess the performance of different organ systems into the body, returning the risk of mortality, based on the relationship between organ failure and mortality. The relationship observed in LIPI and SOFA scores allow us to hypothesize that very low levels of VitD are associated with worst prognosis in COVID-19 patients.
None of the patients studied have had BCG vaccination, patients over the age of 65 had undergone anti-flue vaccination. Although a no-specific protection of vaccination, in particular with BCG, from different viral infections has been reported  the protective role of BCG or other vaccination to protect against COVID-19 infection should be interpreted with caution . Furthermore, no significant difference in COVID-19 spread rate was detected between countries with or without current BCG vaccination policy .
Although an inverse correlation between plasma VitD and all causes of mortality in healthy or general medical clinic cohorts has been described in particular in the lowest quantile (0-9 ng/ml), the effect of VitD deficiency in COVID-19 progression or disease severity is far to be assessed. Our data underline a relationship between VitD plasma levels and different serum markers of disease. At the moment it is difficult to argue if VitD supplementation can play a role in fighting the severity of the disease as well as reducing its mortality, but it may be a useful as well as a safe recommendation for almost all patients.